Each of the trillion neurons in the human brain can have up to 10,000 synapses. By establishing a dynamic network of synaptic connections, the brain is able to attain the level of functional complexity that underlies human behavior. The efficiency of signal transmission at synapses is constantly being adapted in response to experience as encoded by neural activity. This synaptic plasticity is critical for the fine-tuning of brain development as well as higher brain functions such as learning and memory. The plasticity of synapses is modulated and maintained by processes that are sensitive to neuronal activity and cell-cell contact. Trans-synaptic protein interactions induce differentiation of the synapse and regulate the morphology and function of synapses. Release of neurotransmitter regulates the activity of the neuron and activates a variety of second messenger pathways including calcium-signaling systems, which have a central role in regulating both rapid synaptic plasticity and long-term changes in synaptic connections through the activation of gene transcription. These activity-regulated genes then modulate the function of the neuron and can directly affect synapse function. This Center will investigate the inter- and intracellular signaling pathways to and from the synapse that induce synapse formation and differentiation and regulate synaptic efficacy. These signal transduction pathways are initiated at sites of neuronal cell contact by extracellular signals and are then relayed to the nucleus and finally cycle back to the synapse to regulate synaptic function. Specifically three inter-related questions will be addressed: 1) what are the molecular determinants of synapse formation and differentiation; 2) what are the molecular mechanisms by which synaptic activity induces transcription; and 3) how do activity-induced genes feed back to regulate synaptic function. Many neurological and psychiatric diseases result from defects in synaptic transmission. Thus, understanding the mechanisms regulating the formation and modulation of synaptic transmission in the brain is critical for the development of treatments for these diseases.